DESCRIPTION (provided by investigator): Otitis media (OM) is the most common disease seen in pediatric practice and is recognized as a multifactorial disease with complex and interrelated genetic, environmental and infectious etiologies. The long- term objectives of our research group are to elucidate the contribution of infectious pathogens, and their complex interactions with other OM risk factors in the pathogenesis of and recovery from acute otitis media (AOM), and to identify possible strategies for more effective prevention and/or treatment. We have recently found an important association between proinflammatory cytokine gene polymorphisms (TNF1-308 and IL- 6-174) and increased OM susceptibility, and possible modifying effects of environmental factors such as breastfeeding (BF) and cigarette smoke exposure (CSE) on OM susceptibility in polymorphic individuals. During the next funding period, we propose to study further the pathogenesis of virus-induced AOM, specifically on the mechanisms by which genetic risk factors (as represented by TNF1-308 and IL- 6-174 polymorphisms) render the host OM susceptible and whether environmental factors could modify OM risks in children with genetic predisposition. Aim 1: Perform a prospective, case-control study of 300 infants with and without TNF1-308 polymorphism followed to the first AOM episode up to 1 year of age. Subjects will be screened for the gene polymorphism; equal number of polymorphic and normal infants (matched for gender and race) will be enrolled into the study within the first month of life. The dynamics of nasopharyngeal bacterial colonization in the first 6 mos. of life will be studied; symptomatic URI episodes will be monitored for AOM complication. Information on BF, CSE, and DC attendance will be collected prospectively and updated continuously. Incidence of AOM in the first year of life (per cent of cases with at least one episode in the first year) will be compared between polymorphic and normal children groups; modifying effects of environmental risk factors on bacterial colonization, incidence of viral URI and AOM will be assessed. Sample size will also be adequate for parallel comparison between IL- 6-174 polymorphic and normal children. Aim 2: Investigate further the association between several other cytokine/ chemokine gene polymorphisms and OM susceptibility. Archived and new DNA samples from the proposed Study 1 (from OM-susceptible and non-OM susceptible children, n=800) will be tested for 11 cytokine/ chemokine gene polymorphisms using the state-of-the-art microarray technique. Gene polymorphisms will be associated with OM susceptibility; data mining will be used to analyze complex data. Information generated from our studies will be important to public health as it will lay the ground work for the design of innovative approaches to prevent OM, especially in children born with genetic predisposition and those exposed to OM environmental risks.